Karolinska Institutet, Department of Clinical Neuroscience, Karolinska University Hospital, Stockholm, Sweden.
Psychopharmacology (Berl). 2011 Feb;213(2-3):533-45. doi: 10.1007/s00213-011-2165-z. Epub 2011 Jan 15.
The serotonin 5-HT(1B) receptor is a potential target for the pharmacologic treatment of depression. Positron emission tomography (PET) determination of 5-HT(1B) receptor occupancy with drug candidates targeting this receptor in non-human primate and human subjects may facilitate translation of research from animal models and guide dose selection for clinical studies. AZD3783 is a recently developed, orally bioavailable 5-HT(1B) receptor antagonist with potential antidepressant properties.
To determine the relationship between plasma concentration of AZD3783 and occupancy at primate brain 5-HT(1B) receptors using PET and the radioligand [(11)C]AZ10419369.
PET studies with [(11)C]AZ10419369 were performed in three non-human primates at baseline and after intravenous injection of AZD3783. Subsequently, PET measurements were undertaken in six human subjects at baseline and after administration of different single oral doses of AZD3783 (1-40 mg).
After administration in non-human primates and human subjects, AZD3783 reduced regional [(11)C]AZ10419369 binding in a dose-dependent and saturable manner. The AZD3783 plasma concentration required for 50% receptor occupancy (K (i,plasma)) for monkeys was 25 and 27 nmol/L in occipital cortex and striatum, respectively. Corresponding estimates for human occipital cortex and ventral striatum were 24 and 18 nmol/L, respectively.
The potential antidepressant AZD3783 binds in a saturable manner to brain 5-HT(1B) receptors with a similar in vivo affinity for human and monkey receptors. [(11)C]AZ10419369 can be successfully used to determine occupancy at brain 5-HT(1B) receptors in vivo and constitutes a useful tool for dose selection in clinical studies with 5-HT(1B) receptor compounds.
5-羟色胺（5-HT）1B 受体是治疗抑郁症的潜在药物靶点。使用正电子发射断层扫描（PET），在非人类灵长类动物和人类受试者中，通过针对该受体的候选药物，确定 5-HT1B 受体占有率，可以促进从动物模型到临床研究的研究转化，并为临床研究选择剂量提供指导。AZD3783 是一种最近开发的、口服生物利用度的 5-HT1B 受体拮抗剂，具有潜在的抗抑郁特性。
使用 PET 和放射性配体 [(11)C]AZ10419369，确定 AZD3783 的血浆浓度与灵长类动物大脑 5-HT1B 受体占有率之间的关系。
在 3 只非人类灵长类动物中，在基线时和静脉注射 AZD3783 后进行 [(11)C]AZ10419369 的 PET 研究。随后，在 6 名人类受试者中，在基线时和给予不同单口服剂量的 AZD3783（1-40mg）后，进行 PET 测量。
在非人类灵长类动物和人类受试者中，AZD3783 以剂量依赖性和饱和的方式降低了局部 [(11)C]AZ10419369 的结合。灵长类动物枕叶皮质和纹状体中 50%受体占有率（K(i，血浆)）所需的 AZD3783 血浆浓度分别为 25 和 27nmol/L。人类枕叶皮质和腹侧纹状体的相应估计值分别为 24 和 18nmol/L。
潜在的抗抑郁药 AZD3783 以饱和的方式与大脑 5-HT1B 受体结合，对人和猴受体的体内亲和力相似。[(11)C]AZ10419369 可成功用于体内确定 5-HT1B 受体占有率，并为 5-HT1B 受体化合物的临床研究选择剂量提供有用工具。
